The Cytoprotective Role Of Gemcitabine-induced Autophagy Associated With Apoptosis In Hibition In Triple-negative MDA-MB-231Breast Cancer Cells

Triple-negative breast cancer, which is estrogen receptor-negative, progesterone receptor-negative and lack of HER2overexpression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. At present, gemcitabine has been approved by FDA/SFDA to use as a first-line therapeutic drug against advanced or metastatic breast cancer. Thus clarifying the mechanisms underlying gemcitabine-acquired resistance is particularly important for optimal management of triple-negative breast cancer. Some studies have revealed that autophagy found to protect cancer cells from anti-cancer drug-induced death may play a role in the development of drug resistance. However, the relationship between autophagy and gemcitabine treatment in triple-negative breast cancer cells has yet to be defined. Our study clearly shows that gemcitabine is able to induce autophagy in human triple-negative MDA-MB-231breast cancer cells. And the autophagy protects MDA-MB-231cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB-231cells. Furthermore, inhibition of the gemcitabine-induced autophagy by chloroquine shifts the expression of the p53protein, Bcl-2family proteins and the relative Bax/Bcl-XL ratio in favor of promoting apoptosis. These results reveal that apoptosis inhibition might be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that exposed to gemcitabine. Our study thus suggests that the combination of autophagic inhibitor with gemcitabine treatment may represent a promising therapeutic approach with higher efficacy for triple-negative breast cancer patients in clinic. More preclinical trials are needed to further determine the positive effect of autophagy inhibition on gemcitabine efficacy.